Alpha-synuclein May Be Responsible for the Link Between Parkinson's Disease and Melanoma

Rapid Response Innovation Awards, 2011

Objective/Rationale:†Although the association between Parkinsonís disease (PD) and melanoma has been well established, biological explanations are still lacking. PD-causing gene alpha-synuclein is highly expressed in some melanoma tissue/cells and its immunoreactivity in cutaneous peripheral nerves is increased in PD patients. We hypothesize that alpha-synuclein may be one of the points for the link between PD and melanoma. We aim to determine differential effects of alpha-synuclein on dopaminergic neurons and on melanoma cells.

Project Description:†Both the incidence of PD and melanoma is higher in Caucasian than that in black populations, suggesting that reduced melanin may enhance vulnerability for both diseases as skin color is related to melanin production. Whatís more, melanoma cells with increased expression of alpha-synuclein generate no or a very low level of melanin. In this proposal, we hope to demonstrate that in addition to dopamine (DA)-dependent toxicity of alpha-synuclein in dopaminergic neurons, increased expression of alpha-synuclein in melanoma cells inhibits UVB light-induced melanin synthesis. This, in turn, results in potential multiplication and growth of melanoma cells. We will further determine effects of alpha-synuclein on pigmentation genes, such as tyrosinase, which control the process of melanin synthesis.

Relevance to Diagnosis/Treatment of Parkinsonís Disease:††This research will provide insights into the high risk of developing melanoma (but not other cancers) in patients with PD and will address the observation that melanoma patients have an increased risk of PD. The findings will draw attention to the importance of vigilance and early detection of melanoma in patients with PD and may lead to a development of common therapeutic strategies for both diseases by targeting alpha-synuclein.

Anticipated Outcome:†We anticipate that increased expression of alpha-synuclein may interact with dopaminergic system and may inhibit synthesis of melanin, supporting our hypothesis that alpha-synuclein could be one of the most important points for the link between some types of PD and melanoma.

INTERIM PROGRESS REPORT

It has been reported that α-synuclein can interact with tyrosinase (TYR) and inhibit tyrosine hydroxylase (TH). Inhibition of TH may lead to the reduction of dopamine (DA). We have conducted experiments on melanoma and dopaminergic neuronal cells that mainly express TYR and TH respectively. We found that UVB light exposure increased melanin synthesis accompanied by the increase of TYR activity in melanoma cells, both of which were less in α-synuclein expressed melanoma cells, indicating that α-synuclein may inhibit UVB light-induced increase of TYR activity and accordingly the decrease of melanin synthesis. Although α-synuclein over-expression inhibited UVB light-induced increase of TYR activity in dopaminergic neuronal cells, no such changes were observed in melanin content. On the contrary, we found that melanin content was significantly higher in α-synuclein over-expressed neuronal cells than its control cells. It is known that decrease of melanin is one of risk factors for developing melanoma and that DA, neuromelanin and a large amount of irons makes dopamuinergic nigral neurons peculiarly susceptible to oxidative stress conditions, triggering a cascade of oxidative degradation. We believe that the differential effects of α-synuclein on melanin synthesis in melanoma and dopaminergic neuronal cells may contribute to the increased incidence of both diseases.